Cancer accounts for one-fifth of the total mortality in the United States, and is the second leading cause of death. Cancer is typically characterized by the uncontrolled division of a population of cells. This uncontrolled division may involve blood cells, such as various types of lymphomas, or cells that aggregate in or are native to a particular tissue or organ, e.g., solid tumors, such as secondary or primary tumors of the breast, liver, esophagus, stomach, intestines, brain, bone, or prostate.
A variety of treatment modalities have been proposed for cancer therapy. These generally include surgical resection of solid tumors, treatment with radiation, such as x-ray, chemotherapy, immune therapy, and gene therapy. The type(s) of therapy that are selected for a given cancer will depend on such factors as patient age, degree of localization of the cancer, and the type and stage of the cancer. Often the therapy will involve a combination of two or more modalities, such as x-ray therapy in combination with chemotherapy, or with immunotherapy in combination with chemotherapy.
A large number of chemotherapeutic compounds and compositions and strategies have been employed in treating cancers. Many anti-neoplastic compounds are designed to disrupt replication in rapidly dividing cells, or to inhibit a key metabolic link in actively proliferating cells. Although such approaches have met with levels of success in certain types of cancers, or cancers at certain stages, chemotherapy is generally associated with unpleasant to debilitating side effects, such as malaise, nausea, loss of appetite, alopecia, and anemia. Further, compounds which act at the level of cell replication, either by introducing nucleotide analogs into dividing cells, or by disrupting normal replication, have the potential of introducing widespread genetic mutations in normal cells in the subject. In addition, cancer cells may develop resistance to many types of anti-tumor agents, either by limiting uptake of the agent into the cells, or by altering the metabolism of the agent within the cells.
In response to these limitations, attempts to modify chemotherapeutic agents to reduce their side effects, overcome problems of resistance, or improve their targeting to selected tumor sites have been developed. While these efforts have yielded improved therapeutic results in some cases, there remains a need to provide an improved chemotherapeutic agent and method. In particular, such an agent should be effective in killing or inhibiting the growth of cancer cells, should be relatively non-toxic both in terms of side effects and long-term effects on the genetic integrity of the treated subject, and preferably deliverable in a form that allows direct introduction into a tumor or selective targeting to tumors.